In vivo insulin resistance to the action of insulin on glucose disposal is commonly found in obese subjects. Since skeletal muscle is the site of uptake of much of an oral or intravenous glucose load, we have assessed the role of obesity associated changes in skeletal muscle morphology on in vivo "insulin resistance", in Pima Indian and Caucasian men. We have found a significant correlation between capillary density (capillaries/square mm cross-section) in skeletal muscle and in vivo insulin action. This may suggest that the increased diffusion distances created by muscle cell enlargement are part of the mechanism by which obesity is associated with "insulin resistance". Since increased distances for insulin to diffuse will delay its onset of action, these findings also explain why there is a delayed onset of insulin action in the obese. We have also found a correlation between the proportions of muscle fiber types and in vivo insulin action. This confirms the relevance to humans of animal studies that have directly shown that oxidative fibers are more insulin sensitive than glycolytic fibers. Since muscle fiber type proportions appear to be genetically determined, these findings may provide a mechanism for the familial dependence of in vivo insulin action. Since the primary control of muscle fiber type proportions appears to be muscle innervation, the central nervous system is implicated as a determinant of in vivo insulin action. We have also found a correlation of muscle fiber type and body fat distribution which suggests that central obesity may be part of a more generalized syndrome.